PROJECT SUMMARY The use of computed tomography (CT) for medical evaluation for lung cancer screening has resulted in a growing number of patients identified with pulmonary opacities, or lung nodules. Patients with lung nodules are at heightened risk of lung cancer; for those who currently smoke, cessation is the most important strategy available to reduce lung cancer risk. To date, there has been no research on tobacco cessation in lung nodule patients, who may have unique attributes (e.g., anxiety about having a nodule coupled with tobacco dependence) that warrant research for the development of maximally effective tobacco cessation interventions. We thus have designed and propose to evaluate 2 novel behavioral interventions as adjuncts to pharmacotherapy. Intervention 1 is based on a large body of research on gain-framed messages for promotion of smoking cessation, which in this case will be designed and personalized specifically for patients with lung nodules, to increase rates of quitting. Intervention 2 is based on our findings that tobacco cessation leads to improvements in health biomarkers (skin carotenoids, plasma bilirubin), and this information can be fed back to participants to prevent relapse and promote longer-term cessation. Specifically, we will enroll and randomize 276 patients with lung nodules to Intervention 1, consisting of a personalized video and print intervention, emphasizing the benefits (gain-framed) of quitting smoking, to evaluate the hypothesis that this will improve tobacco quit rates above and beyond standard of care smoking cessation treatment over 8 weeks. Then we will perform a second randomization to Intervention 2, an individual-level, biofeedback intervention to examine the hypothesis that this intervention will reduce smoking at 6 months. In addition, we propose to evaluate the impact of smoking cessation on microRNA profiles in human serum, with particular interest in levels of the let-7 family of microRNAs, to better understand the biological mechanisms by which smoking cessation reduces lung tumor promotion and to explore another potential biomarker of cessation. Blood/DNA will also be banked to support future biomarker-based studies. Overall, this project aims to develop transferable interventions to improve short- and longer-term smoking cessation rates in this understudied high- risk patient population, while also evaluating mechanisms involving tobacco carcinogenesis, with clear translational potential.